There are a number of disorders associated with leakage around blood vessels and within the tight junctions between cells. Such leakage can lead to fluid invading the tissues, causing a loss in blood pressure, organ dysfunction or failure, and death. Many of these disorders are a result of massive cell death, such as that associated with chemotherapy of a large tumor, sepsis following systemic bacterial infection, inflammation associated with burns, and large surgical resections.
Severe sepsis results from the body's systemic over-response to infection. This over-response disrupts homeostasis through an uncontrolled cascade of inflammation, coagulation, and impaired fibrinolysis. Deranged micro-circulatory function leads to global tissue hypoxia and direct tissue damage. This ultimately results in organ failure, and often, death. Anti-infectives, resuscitation, and supportive care do not necessarily prevent the progressive organ dysfunction that occurs in many patients. Microcirculatory dysfunction may persist despite adequate global values of oxygen delivery, making resuscitation procedures ineffective.
The “leaky gut” hypothesis proposes that leakage of enteric bacteria into the body resulting from disruption of the epithelial barrier is a critical step in the pathophysiology of various disorders such as inflammatory bowel disease and sepsis.
One third of women undergoing mastectomy with axillary evacuation for primary breast cancer suffer from postoperative seromas leading to unnecessary costs and complications such as infections and new operations. Different methods to prevent seroma formation have been tried without permanent success.
Another condition for which there are insufficient treatments is the loss of fluid which occurs due to sepsis or burns, where the junctions between cells begin to leak interstitial fluid, causing dehydration, electrolyte imbalance, and cell death.
These disorders can lead to further complications when the release of inflammatory molecules from the damaged tissue elicits further tissue damage.
U.S. Pat. Nos. 5,670,483, 6,548,630, and 7,098,028 by Zhang et al. describe amphiphilic peptides having alternating hydrophobic and hydrophilic residues. Zhang alleges that the membranes are potentially useful in biomaterial applications such as slow-diffusion drug delivery systems, artificial skin, and separation matrices, and as experimental models for Alzheimer's disease and scrapie infection. However, Zhang does not disclose the use of such materials for treatment and support of disorders associated with leaky, damaged tight junction and weak, diseased, or injured extracellular matrix.
WO 2007/142757 and U.S. Ser. No. 11/411,745 describe compositions including peptides with alternating hydrophilic and hydrophobic monomers that allow them to self-assemble under physiological conditions are formulated for application to wounds. However, these applications do not describe the use of such materials for treatment and support of disorders associated with leaky, damaged tight junction and weak, diseased, or injured extracellular matrix.
It is therefore an object of the present invention to provide a methods and compositions for treating conditions involving not just fluid leakage but pathophysiology of the junctions between cells.
It is another object of the present invention to provide methods and compositions for increasing extracellular matrix around vascular cells.
It is still a further object of the present invention to provide methods and compositions for repairing or strengthening tight-junctions.